Antiarrhythmic properties of triamterene derivatives in the coronary artery ligated rat model.

Triamterene and several triamterene derivatives were tested for antiarrhythmic activity in the coronary artery ligated and reperfused (CAL-R) rat. The class-III antiarrhythmic drugs (+/-)-sotalol and amiodarone, the class-I antiarrhythmics lidocaine and quinidine as well as the potassium sparing diuretic amiloride were used as reference drugs. Triamterene at the highest dose (30 mumol/kg) revealed a 100% protection against ventricular fibrillation (VF), whereas at 10 mumol/kg no antiarrhythmic activity for triamterene could be found. For compound 4 (10 mumol/kg) a 75% protection against VF could be demonstrated, while 2, 3, and 5 revealed only a 25% protection. Compared to the reference drugs, triamterene and the derivatives 2-5 are more potent than (+/-)-sotalol, but less potent than lidocaine, quinidine and amiodarone. For amiloride as well as for the potent potassium retaining triamterene derivative 6 no antiarrhythmic activity could be shown. Therefore, we conclude different mechanisms responsible for the potassium sparing and antiarrhythmic properties of triamterene and its derivatives.     

Antiarrhythmic properties of antidepressant drugs after coronary artery occlusion and reperfusion in rats

The effects of the intravenously administered antidepressant drugs mianserin, imipramine, metapramine, nomifensine and amineptine against ischaemia and reperfusion arrhythmias were investigated in anaesthetized rats. Imipramine, metapramine, mianserin and high doses of nomifensine (0.5 mg.kg-1) reduced the mortality and the duration of ventricular fibrillation observed following coronary artery ligation. Amineptine was ineffective in preventing early postligation arrhythmias. With the tricyclic antidepressant drugs imipramine and metapramine, the arrhythmias were practically suppressed after 15 min following coronary artery ligation. The incidence of reperfusion arrhythmias was significantly reduced by tricyclic antidepressant drugs. In contrast, amineptine was not effective and did not alter cardiac function. It was suggested that nonspecific effects of these drugs account for their antiarrhythmic action. The most plausible explanation for their antiarrhythmic action may be a quinidine-like cardiac depressant activity.     

Antiarrhythmic properties of some aroxyethylamine derivatives with adrenolytic activity

A series of aroxyethylamines (1-10) have been previously evaluated for antihypertensive and adrenolytic properties. Of the derivatives tested, four (compounds 4, 7, 8 and 10) displayed significant antihypertensive activity and binding affinities for alpha- and beta-adrenergic receptors. As a continuation of our study, we present here the in vivo and in vitro antiarrhythmic activity of compounds 1-10, as well as their electrocardiographic properties. Only compounds 4, 7, 8 and 10 demonstrated strong antiarrhythmic activity in adrenaline induced arrhythmia after intravenous and oral administration. In addition, compounds 4 and 7 significantly decreased heart rhythm disturbances in arrhythmia induced by coronary artery occlusion and reperfusion. The pharmacological results and receptor binding studies suggest that the antiarrhythmic activity of the compounds tested may be related to their adrenolytic properties. Moreover, the presence of a methoxyphenylpiperazine moiety seems to be required for their pharmacological activity.     

Antiarrhythmic and antioxidant activity of novel pyrrolidin-2-one derivatives with adrenolytic properties

A series of novel pyrrolidin-2-one derivatives (17 compounds) with adrenolytic properties was evaluated for antiarrhythmic, electrocardiographic and antioxidant activity. Some of them displayed antiarrhythmic activity in barium chloride-induced arrhythmia and in the rat coronary artery ligation-reperfusion model, and slightly decreased the heart rate, prolonged P-Q, Q-T intervals and QRS complex. Among them, compound EP-40 (1-[2-hydroxy-3-[4-[(2-hydroxyphenyl)piperazin-1-yl]propyl]pyrrolidin-2-one showed excellent antiarrhythmic activity. This compound had significantly antioxidant effect, too. The present results suggest that the antiarrhythmic effect of compound EP-40 is related to their adrenolytic and antioxidant properties. A biological activity prediction using the PASS software shows that compound EP-35 and EP-40 can be characterized by antiischemic activity; whereas, compound EP-68, EP-70, EP-71 could be good tachycardia agents.     

Pirmenol hydrochloride (CI-845): antiarrhythmic profile in coronary artery ligated conscious dogs

The antiarrhythmic profile of CI-845 (pirmenol hydrochloride) was assessed in conscious, coronary artery ligated dogs. In single-dose studies in these arrhythmic dogs, CI-845 administered by the intravenous, intranuscular, and oral routes was highly effective in restoring normal sinus rhythm. A 2.5 mg/kg dose was effective against the arrhythmias occurring on the second day after ligation, while 5 mg/kg was effective against the higher-rate arhythmias of the first day after ligation. The reference agents ajmaline, aprindine, disopyramide, lidocaine, mexiletine, procainamide, and quinidine were also tested, and in this model, CI-845 had greater efficacy, a longer duration of activity, and/or a wider safety margin. In slow rate intravenous infusion studies, 1-2 mg/kg/hr of CI-845 maintained near total arrhythmia conversion in first-day postligation dogs. Rapid rate intravenous infusion studies (10 mg/kg/hr) demonstrated a good correlation between the CI-845 dose, plasma level, and arrhythmia conversion, as well as a wide margin of safety. Mean conversions to 80% normal rhythm were achieved at 2.5 mg/kg, with associated plasma levels of 0.8 +/- 0.1 micron/ml, while first sings or gross toxicity occurred at 21.7 +/- 2.4 mg/kg at plasma levels of 6.2 +/- 0.4 micron/ml. There were minimal effects on cardiac conduction and blood pressure even at large doses. In drug interaction studies, CI-845 was safe and effective in combination with disopyramide, lidocaine, procainamide, propranolol, and quinidine. The results clearly show CI-845 to be an orally effective, long-acting antiarrhythmic agent with a favorable margin of safety in the coronary artery ligated dog model.     

Antioxidant properties of calcium dobesilate in ischemic/reperfused diabetic rat retina.

Calcium dobesilate possesses antioxidant properties and protects against capillary permeability by reactive oxygen species in the rat peritoneal cavity, but whether a similar action can take place in the diabetic rat retina is unknown. We investigated the oral treatment of diabetic rats with calcium dobesilate on the prevention of free radical-mediated retinal injury induced by ischemia/reperfusion (90 min ischemia followed by 3 min and/or 24 h of reperfusion). Streptozotocin-induced diabetic rats were orally treated with 50 and 100 mg/kg of calcium dobesilate for 10 days (n=12 in each group). In the first series of studies, calcium dobesilate was found to significantly reduce the maldistribution of ion content in diabetic ischemic/reperfused rat retina. Thus, in diabetic rats treated with 100 mg/kg/day calcium dobesilate, ischemia/reperfusion provoked: (i) 27.5% increase in retinal Na(+) content compared to 51.8% in the vehicle-treated group (P<0.05), and (ii) 59.6% increase in retinal Ca(2+) content compared to 107.1% in vehicle-treated animals (P<0.05). In the second series of studies, calcium dobesilate was found to significantly protect diabetic rat retina against inhibition of Na(+)/K(+)-ATPase and Ca(2+)/Mg(2+)-ATPase activities by ischemia/reperfusion (54% and 41% reduction, respectively, with 100 mg/kg of calcium dobesilate) and also against changes in retinal ATP, reduced glutathione (GSH), and oxidized glutathione (GSSG) contents. In the third series of experiments, rats treated with 100 mg/kg of calcium dobesilate reduced the hydroxyl radical signal intensity to 41% (measured by electron paramagnetic resonance), induced by ischemia/reperfusion in diabetic rat retina. Finally, 100 mg/kg calcium dobesilate significantly reduced retinal edema (measured by the thickness of the inner plexiform layer) in diabetic rats. In conclusion, oral treatment with calcium dobesilate significantly protected diabetic rat retina against oxidative stress induced by ischemia/reperfusion. Whether the antioxidant properties of calcium dobesilate explain, at least in part, its beneficial therapeutic effects in diabetic retinopathy deserves further investigation.     

Antiarrhythmic and antihypertensive activity of some xanthone derivatives

Some of appropriate aminoisopropanoloxy derivatives of 4-xanthone were tested for their effect on circulatory system (protection against adrenaline-, barium-, and calcium chloride-induced arrhythmias, as well as hypotensive activity and acute toxicity). The most prominent hypotensive activity was demonstrated by (+/-)-1-[4-(hydroxyethyl)-1-(piperazinyl)]-3-(4-xanthonoxy)-2-propanol dihydrochloride (II), which diminished arterial blood pressure by about 40% during one hour observation. The investigated compounds did not prevent adrenaline- and barium-induced arrhythmias. In calcium-induced model of arrhythmia compound II slightly intensified blocks (about 7%), but delayed extrasystoles (37%), efficiently prevented bigeminy (70%, p <0.01) and diminished (53%, p <0.05) mortality of animals. All investigated compounds decreased heart rate by 10 - 18%, prolonged P-Q section, QRS complex and Q-T interval. The most potent and significant negative chronotropic effect and markedly prolonged duration of P-Q section was demonstrated by compound II. The influence of investigated compounds on ECG components suggests that activity of compound IV is similar to class 1a anti-arrhythmic compounds according to Voughan-Williams classification of antiarrhythmic drugs, because of prolongation of P-Q and Q-T intervals and extension of QRS complex. Compounds II and IV were also evaluated for anticonvulsant activity in the maximal electroshock seizures (MES) and subcutaneous pentylenetetrazole seizure threshold (ScMet) assays and for neurotoxicity (TOX). The anti-MES activity in mice was found for IV, which in a dose of 100 mg/kg within 0.5 h after ip administration showed 75% anticonvulsant protection with 50% neurotoxicity.     

Antiarrhythmic activity of heptacaine and some of its derivatives

In the evaluation of experimental antiarrhythmic effect in guinea pigs, by a method of antagonizing ouabain arrhythmogenity, there was found a maximum effect of N-[2-(2-heptyloxy-phenylcarbamoyloxy)-ethyl]-piperidinium-chloride (heptacaine). The shortening or prolongation of the alkoxy substitution in the ortho-position, or the shift of hexyloxy substitution to the meta- or para-position, respectively, causes a decrease in activity. Negative chronotropic effect of heptacaine is increased and prolonged during the 5th min after acute i.v. application. The effect of lidocaine was short-lasting and decreased. In antagonizing experimental adrenaline (epinephrine) arrhythmogenity, heptacaine showed an important antiarrhythmic effect, too. In the relative hypotensive activity evaluation, there was an important effect in the 1st min after i.v. application and this decreased to the same values as those of lidocaine in the 5th min. Hypotensive effect evaluation of lidocaine and heptacaine after higher doses than therapeutic ones showed that the hypotensive effect of heptacaine takes place at the same rate as that of lidocaine and by the 10th min reaches control values. Values of experimental partition coefficient showed an increase in relation to prolongation of ortho-alkoxy substitution in the sequence: propoxy less than pentyloxy less than heptyloxy less than nonyloxy. Submaximal value by the heptacaine may reflect an optimal hydrophylic-lipophylic balance of its molecule. But in the evaluation on antiouabain effect and partition coefficient, there is no simple direct correlation in structure-activity relationship.     

Antiarrhythmic profile and endothelial action of novel decahydroquinoline derivatives

We tested antiarrhythmic and endothelial action of novel decahydroquinoline derivatives. Antiarrhythmic activity was analyzed using models of aconitine-, calcium chloride-, and adrenaline-induced arrhythmias in rats. Potency to induce nitric oxide (NO)-dependent coronary vasodilation was assessed in isolated guinea pig heart perfused according to Langendorff technique. Among 15 novel decahydroquinoline derivatives (D1-15), four of them displayed antiarrhythmic activity (D12-D15). D12-D15 compounds were more active in the model of aconitine-induced arrhythmias than in calcium chloride-induced arrhythmias and were inactive in the model of adrenaline-induced arrhythmias. Profile of antiarrhythmic activity of D12-D15 compounds was similar to that of quinidine and procainamide. Interestingly, in the isolated guinea pig heart D14 and D15 (10(-5) M) induced coronary vasodilation, that was mediated by endothelium-derived NO. In conclusion, novel decahydroquinoline derivatives described here (D12-D15) show antiarrhythmic activity typical of antiarrhythmic drugs of class I. Importantly, some of these compounds (D14, D15) release NO from coronary endothelium, which may provide an additional therapeutic benefit.     

Antiarrhythmic properties of the anticonvulsant drug benzonal

In experiments on albino rats benzonal was found to exert an antiarrhythmic effect on models of chloride calcium-, aconitine- and strophantine-induced arrhythmias. In chloride calcium- and aconitine-induced arrhythmias its effect was qualitatively similar to that of diphenine, however it was inferior by the value of ED50 as compared with the latter. The advantage of benzonal over diphenine was its low toxicity.     

Effect of inosine in the normal and reperfused rat heart.

Inosine is a positive inotropic agent and dilates coronary blood vessels. During ischemia, inosine infusion increases blood flow, resulting in decreased myocardial damage. We wished (a) to determine inosine's effect in isolated rat hearts and (b) to determine if inosine attenuates myocardial dysfunction after transient global ischemia. Developed left ventricular pressure (LVP), LV dP/dt, and coronary perfusion pressure were monitored in hearts receiving Krebs-Henseleit buffer (KHB) (n = 10) or KHB + 2 mM inosine (n = 4). KHB + 2 mM inosine significantly reduced coronary perfusion pressure by 21% but had no effect on developed LVP or LV dP/dt. Hearts receiving KHB (n = 6) or KHB + 2 mM inosine (n = 5) were subjected to 15-min global ischemia followed by 30-min reperfusion with KHB. Recovery of LVP, LV dP/dt, the incidence of arrhythmias, and the time to peak recovery of developed LVP was not different between groups. In two additional hearts, KHB + 2 mM inosine administered during reperfusion had no effect on developed LVP, LV dP/dt, or coronary perfusion pressure. Thus, unlike other preparations, inosine pretreatment did not significantly affect the time course of postischemic functional recovery of rat myocardium.     

麝香保心分散片对冠脉结扎犬血流动力学的影响

目的研究麝香保心分散片对冠脉结扎犬血流动力学的影响。方法采用麻醉犬开胸结扎左冠状动脉前降支 (LAD)产生急性心肌梗死 (AMI)模型 ,测定AMI 3h犬的心脏血流动力学参数。结果十二指肠给予麝香保心分散片 ,能明显增加心输出量 (CO)和搏出量 ,增加心肌血流量 ,降低冠脉阻力 ,增加左室收缩内压 (LVSP)及室内压最大上升和下降速率 (±dp/dtmax) ,轻度减慢心率 ,明显降低左室舒张末期压 (LVEDP) ,增加冠脉结扎犬心脏指数 (CI)及搏功 ,降低总外周阻力 ,对平均动脉压有下降趋势。结论麝香保心分散片主要以改善心肌收缩和舒张功能 ,增加缺血心肌供血等环节 ,发挥抗心肌缺血作用     

Antiarrhythmic properties of opioid receptor agonists

Data on the antiarrhythmic properties of opioid receptor (OR) agonists have been systematized. An analysis of published works which indicate that opioids increase cardiac tolerance to arrhythmogenic influences both in vivo and in vitro has been performed. For example, occupancy of central micro- and delta-OR and also ORL1 receptors increases cardiac tolerance to arrhythmogenic action epinephrine and aconitine. In contrast, activation of central kapa-OR exacerbates arrhythmogenic action epinephrine. Stimulation of peripheral delta2- and kappa1-OR decreases an incidence of arrhythmias induced coronary artery occlusion and reperfusion in vivo. Occupancy of peripheral micro-, kappa2-, delta1-OR and also ORL1 receptors has no effect on the cardiac tolerance to arrhythmogenic action of ischemia and reperfusion but increases cardiac electrical stability in rats with post-infarction cardiosclerosis. Authors suggest that opioids which unable penetrate to blood barrier may be used for therapy of arrhythmias.     

Antiarrhythmic actions of verapamil against ischaemic arrhythmias in the rat

The actions of intravenous verapamil against arrhythmias induced by occlusion of a coronary artery were investigated in conscious rats. Verapamil (2-20 mg kg-1, i.v. given pre-occlusion) dose-dependently reduced arrhythmias in rats with either large or small occluded zones at an ED50 of 6 mg kg-1. This dose was effective when given immediately post-occlusion. Severe arrhythmias, as opposed to PVC, were preferentially reduced. In conscious, and pentobarbitone-anaesthetized rats, verapamil (6 mg kg-1) had different effects on electrically-induced arrhythmias, and the ECG, from an equi-effective anti-arrhythmic dose of quinidine (20 mg kg-1, i.v.). Quinidine decreased following frequency, but increased threshold current and pulse width, whereas verapamil did not. Both drugs increased P-R interval, but only quinidine increased QRS and Q-T intervals. Thirty minutes post-occlusion, the verapamil content of tissue and blood was determined after a 6 mg kg-1 dose given pre- or post-occlusion. Measurable levels of verapamil were found in both normal and ischaemic myocardium. Plasma and plasma water concentrations were 3.6 +/- 0.8 mumol l-1 and 0.6 +/- 0.1 mumol l-1 (mean +/- s.e. mean), respectively following post-occlusion administration vs. 2.7 +/- 1.2 and 0.24 +/- 0.04 for pre-occlusion administration. Plasma water concentrations were close to IC50 values for inhibition of contractility in rat atria and ventricles. Similar concentrations depressed slow action potentials induced in rat ventricles by raised K+ We suggest that the ability of verapamil to prevent severe ventricular arrhythmias following myocardial ischaemia in the conscious rat is largely due to the calcium antagonist effects of the drug.     

Antifibrillatory properties of alinidine after coronary artery occlusion in rats

Ligation of the left anterior descending coronary artery was performed in open-chest anaesthetized rats and mortality as well as changes in ECG were evaluated for 30 min thereafter. Saline or drugs were administered 15 min prior to ligation. In the control group, following a 4 min lag period ventricular arrhythmias as single ectopic beats, ventricular tachycardia and ventricular fibrillation (VF) appeared, reaching a maximum between 10 and 20 min and disappearing after 30 min. Mortality (40% in the control group) coincided with the period of maximal arrhythmias, with VF more common in animals that died than in those surviving. Alinidine, a drug which reduces sino-atrial rate specifically but has no conventional antiarrhythmic properties, reduced mortality and VF. By means of order statistics the quantity ‘risk of death’ was used for evaluation of drug effects, considering incidence of death and VF as well as duration of VF. This quantity was reduced in correlation with the dose of alinidine (1–6 mg/kg i.v.) and in correlation with the reduction of heart rate. Mexiletine, an antiarrhythmic drug with membrane-depressant properties, also reduced the ‘risk of death’ dose dependently (1–10 mg/kg i.v.), but there was no correlation with a decrease in heart rate. It is suggested that alinidine reduced ‘risk of death’ by means of a reduced oxygen demand due to a decrease in heart rate.     

Mechanisms of the dilator action of cryptotanshinone on rat coronary artery

In this study, we have investigated the actions of cryptotanshinone, an active, lipophilic component of the medicinal herb danshen (Salvia miltiorrhiza), on rat isolated coronary artery rings precontracted with 1 microM 5-hydroxytryptamine (5-HT) and its action compared to the ethanol-extractable fraction of the herb. Extraction of the ethanol-soluble fraction from danshen provided a yield of 1%. The amount of cryptotanshinone determined in this ethanol extract was 3.682%, and it was 6 times more potent than the extract in relaxing 5-HT-precontracted coronary artery rings; IC(50) values were 2.65+/-0.15 microg/ml and 15.82+/-1.07 microg/ml, respectively. Involvement of endothelium-dependant mechanisms in their dilator effects were investigated by pretreatment of the artery rings with a cyclooxygenase inhibitor flurbiprofen (10 microM), a nitric oxide synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME, 100 microM), a muscarinic receptor antagonist atropine (100 nM), and by mechanical removal of the endothelium; none of these procedures produced a significant change on their dilator actions. Involvement of endothelium-independent mechanisms was investigated in endothelium-denuded artery rings pretreated with a beta-adrenoceptor antagonist propranolol (100 nM), an adenylyl cyclase inhibitor 9-(tetrahydro-2-furanyl)-9H-purine-6-amine (SQ22536, 100 microM), a guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 10 microM), and a potassium channel inhibitor tetraethylammonium (TEA, 100 mM); these also produced no change on their dilator actions. The possible involvement of Ca(2+) channels was investigated in artery rings incubated with Ca(2+)-free buffer and primed with 1 microM 5-HT for 5 min prior to adding CaCl(2) to elicit contraction. The danshen ethanol extract (100 microg/ml) abolished the CaCl(2)-induced vasoconstriction, whereas, cryptotanshinone (30 microg/ml) produced 59% inhibition. These findings suggest their vasorelaxant effects are independent of pathways mediated by the endothelium, muscarinic receptors, beta-adrenoceptors, adenylyl cyclase, and guanylyl cyclase, whereas, inhibition of Ca(2+) influx in the vascular smooth muscle cells is important for their vasodilator actions. The high vasodilator potency and the quantity of salvianolic acid B contained in danshen ethanolic extract suggest it is an important constituent in this medicinal herb.